In recent years an ultradian pulsatile secretory pattern has been described for a number of hormonal systems long thought to behave in a strictly homeostatic manner. Despite the increasing awareness of this secretory phenomenon relatively little information is available about its functional significance. The possibility that pulsatile stimulation in some way enhances target tissue responsiveness is both intrinsically interesting and of possible therapeutic importance. Our laboratory which has been actively involved in the field of fuel metabolism for many years first described the existence of an ultradian islet secretory cycle in primates in 1977. Drawing upon this extensive research experience I propose to examine the consequences of cycle islet secretion at three levels. First, I will extend in vitro studies of single cell types begun as a research fellow of the Washington Affiliate of the American Diabetes Association. To date these studies have clearly demonstrated an enhanced hepatocyte sensitivity to pulsatile as opposed to continuous glucagon administration. With the assistance of Dr. Christoph de Haen of the University of Washington Departments of Medicine and Biochemistry, similar studies will be performed on adipocytes looking for pulse-enhancement of insulin effects. Cultured mouse myoblasts will be used as yet another cell type representative of the peripheral compartment in the in vitro portion of these studies. In the second phase of the proposd work the effects of pulsatile and continuous administration of insulin and glucagon to non-human primates will be investigated. These studies will use the extensive facilities of the Regional Primate Research Center. The dose-response characteristics for the two modes of hormone administration wil be investigated using both somatostatin-treated and streptozotocin diabetic animals. In the third phase of the proposed work the possible pathophysiological role of pulsatile islet hormone secretion in diabetes mellitus will be examined. Initial studies will involve the collection of timed serum samples in an attempt to correlate the ampliltude and frequency of the glucagon cycle with the brittleness of control in type 1 diabetics.